(R-(E))-1-(((1-(3-(2-(7-chloro-2-quinolinyl)ethenyl)phenyl)-3-(2-(1-hydroxy-1-methylethyl)phenyl)propyl)thio)methyl)cyclopropaneacetic acid sodium salt, also known by the name montelukast sodium, is represented by the structural formula I below:

Montelukast sodium is a leukotriene antagonist, and is thus useful as an anti-asthmatic, anti-allergic, anti-inflammatory and cytoprotective agent. Montelukast sodium is currently indicated for the treatment of asthma and allergic rhinitis.
Montelukast sodium, formulated as tablets (containing 10.4 mg montelukast sodium), chewable tablets (containing 4.2 or 5.2 mg montelukast sodium) or oral granules (in a packet containing 4.2 mg montelukast sodium), is typically given once daily to the patients for the treatment of asthma and seasonal allergic rhinitis. Montelukast sodium is marketed in the United States and other countries by Merck & Co., Inc. under the trade name Singulair®.
Montelukast sodium and related compounds were first disclosed in European Patent No. EP 480,717. The synthesis of montelukast sodium, as taught in patent EP 480,717, involves coupling methyl 1-(mercaptomethyl)cyclopropaneacetate (IIa) with 2-(2-(3(S)-(3-(7-chloro-2-quinolinyl)ethenyl)phenyl)-(methanesulfonyloxypropyl) phenyl-2-propanol (III) followed by hydrolysis of the resulting montelukast methyl ester so as to form a free acid, which is followed by conversion of this montelukast free acid to a corresponding sodium salt, isolated as an amorphous material by freeze-drying.
U.S. Pat. No. 5,523,477 describes the formation of montelukast and its subsequent conversion into the dicyclohexyl ammonium salt, which is converted to montelukast sodium.
U.S. Pat. No. 5,614,632 teaches a method of preparing crystalline montelukast sodium, which involves the preparation of the dilithium dianion of 1-(mercaptomethyl)cyclopropaneacetic acid (IV), using butyl lithium, followed by condensation thereof with the mesylate alcohol (III) to yield montelukast acid as a viscous oil. The resulting montelukast acid is converted, via the corresponding dicyclohexyl ammonium salt, to crystalline montelukast sodium.
The extra purification step via the dicyclohexyl ammonium salt, which is disclosed in U.S. Pat. Nos. 5,523,477 and 5,614,632, is necessitated from the difficulties encountered in obtaining crystalline materials. Thus, the crude acid is purified via the dicyclohexylamine salt by reacting it with dicyclohexylamine in ethyl acetate, followed by addition of hexanes to effect crystallization of the dicyclohexylamine salt, or by the crystallization from toluene/heptane. It is mentioned by the inventors of patent U.S. Pat. No. 5,614,632, that the crystalline montelukast dicyclohexylamine salt offers an efficient method for the purification of montelukast, which circumvents the need to use chromatographic purification.
Another process for preparing montelukast sodium is provided in patent application WO 2005/105751 (hereinafter the '751 application). It is stated in the '751 application that butyl lithium is a dangerous and expensive material, hence there is a need for another method which avoids the use of this reagent. Thus, the '751 application provides a process for preparing montelukast sodium comprising reacting 2-(2-(3(S)-(3-(7-chloro-2-quinolinyl)ethenyl(phenyl)-3(hydroxypropyl)phenyl-2-propanol (V) with methanesulfonyl chloride to obtain 2-(2-(3(S)-(3-(7-chloro-2-quinolinyl)ethenyl)phenyl)-(methanesulfonyloxypropyl)phenyl-2-propanol (III), which is subsequently reacted with 1-(mercaptomethyl)cyclopropaneacetic acid alkyl ester (e.g., compound IIa or IIb) in a solvent and in the presence of a co-solvent and a base such as NaOH, followed by hydrolysis of the resulting product of the previous step to obtain montelukast sodium.
The synthesis of the 1-(mercaptomethyl)cyclopropaneacetic acid alkyl esters, according to the '751 application, as taught in examples 1 and 2 therein, is depicted in Scheme 1 below.

However, using one of the reagents belonging to the group of compounds 1-(mercaptomethyl)cyclopropaneacetic acid alkyl esters adds an extra synthetic step to the total synthesis of montelukast sodium, because these esters are obtained from the corresponding 1-(mercaptomethyl)cyclopropaneacetic acid.
Thus, there is still a need in the art for a method of preparing montelukast sodium, which has no additional synthetic steps in comparison to the original process described in patent U.S. Pat. No. 5,614,632 on one hand, and avoiding the use of butyl lithium on the other hand.